In 1915, she exhibited at the RHA, contributing
more than 60 artworks over the next 40 years, many of them portraits.
In 1924, she won the Tailteann gold, silver and bronze medals. In 1928
she won another Tailteann bronze, a feat she repeated in 1932.

Margaret Clarke's many commissions included
portraits (produced in charcoal
as well as oils) of Dermod
O'Brien, President of the Royal Hibernian Academy (1935), Dr Edward
Sheridan, President of the Royal College of Surgeons in Dublin (1946),
and the painting "St Patrick Climbs Croagh Patrick" (Dublin,
Mansion House, 1932). However, Clarke's reputation rests on landscapes
and small-format subject paintings like flowerpieces as well as the portrait
of Lennox Robinson (1926) and the portrait of Harry Clarke (c.1932). Clarke
also produced a number of pictures that were strongly influenced by William
Orpen, such as "Strindbergian" (1927). In 1930 she was commissioned
to design a poster for the Empire Marketing Board.